Nectin-4 PET for predicting enfortumab vedotin dose-response in urothelial carcinoma

作者：Akhilesh C. Mishra, Ajay Sharma, Kuldeep Gupta, Dhanush S. Banka, Burles Avner Johnson, Hoffman-Censits Jean, Peng Huang, David James McConkey, Sridhar Nimmagadda · 发表于：Science Advances · 年份：2026 · DOI：10.1126/sciadv.ady1111 · 被引用次数：11 · 研究领域：Bladder and Urothelial Cancer Treatments、Wnt/β-catenin signaling in development and cancer、HER2/EGFR in Cancer Research

Optimizing dosing strategies is critical to balance effectiveness and toxicity, especially for drugs with narrow therapeutic windows such as antibody-drug conjugates (ADCs). This study evaluates whether positron emission tomography (PET) imaging targeting Nectin-4 can noninvasively quantify the real-time interaction of the ADC enfortumab vedotin (EV) with tumors in urothelial carcinoma. Using the imaging agent [ 68 Ga]AJ647, dynamic changes in the interaction of EV with Nectin-4 were measured across preclinical models and correlated with therapeutic responses. PET imaging identified dose-dependent variations in Nectin-4 engagement, with suboptimal EV doses resulting in incomplete Nectin-4 engagement and increased tumor growth. Crucially, PET-measured target engagement predicted therapeutic outcomes more reliably than either drug dose or baseline target expression. By defining effective target engagement levels needed for optimal therapeutic outcomes, PET imaging provides a clear benchmark for dosing decisions, maximizing efficacy while potentially reducing exposure to higher, toxic doses and thereby enhancing patient safety.